Primary hyperparathyroidism
and
indications for surgery
Jennifer L Marti, MD
Endocrine Surgery
Beth Israel Medical Center
Mount Sinai Health System
New York, New York
Hyperparathyroidism
Overview
1. PHPT is underdiagnosed
2. Evidence for the guidelines
3. Are the guidelines absolute?
Hyperparathyroidism
Diagnosis & initial evaluation
Hyperparathyroidism
PHPT: blood test diagnosis
Excessive secretion of PTH inappropriate to the serum
calcium concentration
10-20% of patients have normal serum calcium levels
Calcium & PTH levels fluctuate… repeat labs
Maruani, JCEM 2003
Hyperparathyroidism
Serum Ca/PTH relationship
Inverse relationship
Khairallah, Nat Clin Pract Nephrol 2007
Hyperparathyroidism
PHPT epidemiology
3 : 1 female : male
2% post-menopausal women (Swedish study)
80-90% single adenoma
5% double adenoma
10-15% 4-gland hyperplasia
Silverberg, Nature Clin Prac Endoc & Metab 2006
Hyperparathyroidism
Action of PTH
Pi: Phosphate
Goltzman, Diseases of Bone and Mineral Metabolism 2008
Hyperparathyroidism
CASE
A 51 year old woman with osteopenia has bloodwork done:
calcium of 9.8 (nl 8.6-10.2),
PTH 82 (nl 10-65)
creatinine 0.8.
Differential Diagnosis? Is this HPT?
PHPT (normocalcemic or classic) or secondary HPT
Workup?
Check another Ca (levels can fluctuate), vitamin D level, 24h
urine calcium
Hyperparathyroidism
Types of hyperparathyroidism
• Primary (normal creatinine)
• Secondary (hypocalcemic or normocalcemic)
– ESRDlow vitamin D, elevated PO4
– Vitamin D deficiency
– Malabsorption, short gut syndrome, gastric bypass
• Tertiary (hypercalcemic)
– Classically described after renal transplant
– Progression of secondary to autonomously
hyperfunctioning glands
Hyperparathyroidism
What is “asymptomatic HPT”?
Lack of specific symptoms or signs
traditionally associated with PHPT, such as:
– Renal stones
– Myopathies
– Osteofibrosis cystica
Bilezikian, JCEM 2009
Hyperparathyroidism
Incidental finding on “routine blood work”
• No longer the classic syndrome of “bones, stones,
groans, and psychiatric overtones”
• Most patients are asymptomatic
• Use of multichannel blood autoanalyzer in 1970s
*
St Goar, Ann Int Med 1957
Silverberg, Nature Clin Prac Endoc & Metab 2006
Hyperparathyroidism
Ask about…
• Nephrolithiasis
• T score, history of fractures
• Neurocognitive symptoms
Hyperparathyroidism
“But doc, I feel fine…”
Incidental hypercalcemia on
“routine blood work” performed
by PCP
Workup reveals PHPT
Who benefits from surgery?
Hyperparathyroidism
CASE
55F with Ca 10.9, PTH 72, normal creatinine.
24h urine 420 mg
T -2.1 lumbar spine
Asymptomatic
Diagnosis?
PHPT
Does she meet consensus guidelines for surgery?
NO (but many would offer surgery)
What are the guidelines for surgery?
Hyperparathyroidism
Rationale for guidelines
Majority of patients are asymptomatic
This led to the Consensus Development Conference on the
Management of Asymptomatic Primary Hyperparathyroidism
at the National Institutes of Health (1990)
Revised in 2002, 2008 & 2013 (Florence, Italy, manuscript in press)
Khan, JCEM 2009
Hyperparathyroidism
Bilezikian, JCEM 2009
Hyperparathyroidism
Third international workshop
on the management of
asymptomatic hyperparathyroidism
Updated in 2013…
Renal ultrasound to screen for kidney stones
Additional skeletal testing
Algorithm for treatment of normocalcemic HPT
Bilezikian, JCEM 2009
Hyperparathyroidism
Evidence supporting the guidelines
Hyperparathyroidism
Evidence supporting the guidelines
Exhibit A:
The natural history of
primary hyperparathyroidism
Hyperparathyroidism
Rubin, JCEM 2008
Hyperparathyroidism
15 year observational study of
patients with primary HPT
Rubin, JCEM 2008
Hyperparathyroidism
Observational study of patients
with primary HPT
Calcium slowly increased over 15 years
Rubin, JCEM 2008
Hyperparathyroidism
Observational study of patients with
primary HPT
Observed
Surgery
57 (49%)
59 (51%)
Recurrence in 100%
(of those with prior stones)
No recurrences
Femur/radius BMD
-10%/-35% (in 59%)
+10%/+7%
0.002
Lumbar spine BMD
Stable
+12%
0.02
Number
Kidney stones
p
At 15 years, surgical patients had increased BMD despite expected agerelated bone loss
These data argue for early surgical intervention
Rubin, JCEM 2008
Hyperparathyroidism
Observational study of patients with
primary HPT
• 37% of asymptomatic patients eventually satisfy criteria
for surgery (1990 criteria)
• This number would likely be higher by the 2008 criteria
• 60% of observed patients continued to lose BMD
• 100% of the surgical group had increased BMD
Rubin, JCEM 2008
Hyperparathyroidism
PEAR study (Scotland)
Yu, QJM 2011
Hyperparathyroidism
PEAR study
1100 patients: mild primary hyperparathyroidism
Tayside, Scotland (1997-2006)
904 observed (median calcium 10.5 mg/dl, PTH 61 pg/mL)
200 had surgery
Followup: 4.7-5.8 years
15% with increasing calcium
• Age at diagnosis and baseline PTH were predictors of hypercalcemia
Yu, QJM 2011
Hyperparathyroidism
PEAR study
Rates per 100 person-years
Surgery decreased the risk of:
Kidney stones (by 88%)
Fractures (by 50%, not significant, underpowered)
Yu, QJM 2011
Hyperparathyroidism
• Danish cohort study (3213 patients; 1980-1999)
– 1934 (60%) underwent surgery
– 1279 (40%) were observed
• Lower risk of fractures, ulcers and death in the surgical group
Vestergaard, BMJ 2003
Hyperparathyroidism
Randomized controlled trials for
asymptomatic primary HPT
Henry Ford Hospital.
Rao. JCEM. 2004.
Pisa.
Ambrogini. JCEM. 2007
Sweden.
Bollerslev. JCEM. 2009.
Meta-analysis.
Sankaran. 2010. JCEM 2010.
N
Observation
Surgery
53
BMD loss:
0.6% / year
Increase in BMD:
1.2% / year
Improved QOL (at 2 yrs)
Improved psych function
50 with mild
disease
(did not meet
1990 criteria)
BMD loss (hip)
Increased BMD (at 1 yr)
Improved QOL (at 1 yr)
23% met criteria
for surgery at 1
year
191
Decreased BMD
Worse QOL
Increased BMD (at 2 yrs)
34 publications
BMD loss:
0.6-1.0% / year
Increased BMD:
2% L-spine
7% femur
Benefits to surgery are observed relatively soon
These RCTs argue for early intervention
Hyperparathyroidism
What about fracture risk?
• Degree of osteoporosis predicts fracture risk
• Primary HPT  increased fracture risk in all patients
• Postoperative data conflicting; many studies underpowered
10 Year Fracture Free Survival Rates
T score
Surgical group
(n=159)
Observed
(n=374)
Absolute risk
reduction
p
> -1.0
98%
89%
9%
NS
-1 to – 2.5
92%
80%
12%
NS
<-2.5
82%
70%
12%
.02
All
94%
81%
13%
.006
Number needed to treat: 8
Vanderwalld, World J Surg 2009
Hyperparathyroidism
GFR < 60 ml / min
•
•
•
•
PTH increases with decreased GFR
This may worsen the primary hyperparathyroid state
Recent data indicates that PTH increases at GFR < 30 ml/min
Increased surface erosion of bone with decreased GFR
Fajtova, Calcif Tissue Int 1995
Tassone, JCEM 2009
Walker, JCEM 2012
Hyperparathyroidism
24 hour urine: no longer a criterion
• Hypercalciuria is not a risk factor for nephrolithiasis
in PHPT (if the patient has never had a kidney stone)
• Still helpful in initial evaluation, to rule out familial
hypocalciuric hypercalcemia
Bilezikian, JCEM 2009
Peacock, J Bone Min Res 2002
Hyperparathyroidism
Age < 50
Increased lifetime in which sequelae will occur
Young age (<50) is associated with increased risk of progression
Rubin, JCEM 2008
Bilezikian, JCEM 2009
Silverberg, Am J Med 2002
Hyperparathyroidism
Are the guidelines absolute?
Hyperparathyroidism
CASE
60 yo woman with calcium 10.9, PTH 65.
Symptoms: depression, memory loss, and fatigue.
Operate or observe?
Hyperparathyroidism
Are 80% of patients really “asymptomatic”?
• With standardized questioning, 80-98% of patients with
“asymptomatic HPT” are symptomatic
• Many of these “symptoms” are vague and non-specific
Clark, J of Bone and Min Res 1991
Eigelberger, Annals Surgery 2004
Hyperparathyroidism
Are 80% of patients really “asymptomatic”?
• Several studies suggest that surgery improves neurocognitive
symptoms in up to 80% of patients
• Reduced mood and anxiety symptoms and improved visuospatial
working memory in a prospective study
• May be placebo effect; follow-up time is short
• The data are not definitive, and are not part of the guidelines
Clark, J of Bone and Min Res 1991
Eigelberger, Annals Surgery 2004
Roman, Sosa, Surgery 2005
Roman, Sosa, Ann Surg 2011
Hyperparathyroidism
Are the guidelines cost-effective?
Parathyroidectomy is more cost effective than observation…
if life expectancy greater than 5 years
Zanocco, Surgery 2009
Hyperparathyroidism
Are guidelines being followed?
•
•
•
•
Kaiser Permanente (1995-2008, n=3388)
Of patients who met guidelines, < 50% had surgery
Of patients not meeting guidelines, 16% had surgery
Of patients with nephrolithiasis, only 50% had surgery
• Parathyroidectomy is underutilized
Yeh, Annals of Surgery 2012
Hyperparathyroidism
Why aren’t the guidelines
being followed?
• Lack of knowledge of the guidelines
• Lack of consultation with a surgeon
• Lack of localization may incorrectly lead to continued observation
• Patients with biochemically-proven PHPT should be referred to a
parathyroid surgeon for consultation
• A surgeon is the ideal individual to explain the risks, benefits and
alternatives to operative intervention
Yeh, Annals of Surgery 2012
Udelsman, JCEM 2009
Hyperparathyroidism
Normocalcemic
hyperparathyroidism
Hyperparathyroidism
Normocalcemic PHPT
Rule out elevated PTH due to
– 25-OH vitamin D deficiency (<20-30 ng/mL)
• Treat with vitamin D, PTH will decrease
– Primary renal calcium leak
• Treat with HCTZ, PTH will decrease
– Impaired kidney function/ESRD
– Low calcium diet, malabsorption
• Treat with calcium, PTH will decrease
Bilezikian, Arq Brs Endoc Metab 2010
Hyperparathyroidism
Do patients with normocalcemic HPT benefit
from surgery?
Controversial, probably yes
Cured of recurrent nephrolithiasis
Expect that patients with nephrolithiasis & osteoporosis
would benefit
Johansson, Surgery 1975
Ljunghall, Acta Chir Scand 1980
Maruani, JCEM 2003
Hyperparathyroidism
Do asymptomatic patients with normocalcemic HPT
benefit from surgery?
Can we apply the 2008 consensus guidelines for
patients with asymptomatic HPT to patients with
NHPT?
Unclear…perhaps in a young patient with osteopenia
Hyperparathyroidism
With normocalcemic HPT…
Is there an easy way to diagnose HPT?
Hyperparathyroidism
Regression model for PTH levels
• Model helps distinguish primary vs secondary HPT
• Based on age, calcium, PTH and Vitamin D levels
• Expected PTH (pg/ml) =
120– (6 * Ca mg/dl)– (0.52 x 25-OH Vit D ng/ml) + (0.26 x age)
• Validated on an independent cohort, successfully identified
– 100% hypercalcemic PHPT
– 96% normocalcemic HPT
Harvey, Endocrine Practice 2011
Hyperparathyroidism
Secondary HPT
Hyperparathyroidism
ESRD/HPT Indications for surgery
• Patients with severe HPT who fail medical therapy
(Sensipar, Vitamin D, Phosphate binders) or
cannot perform surveillance
• Persistently hypercalcemic
• PTH >800 pg/mL
• Calciphylaxis , fractures, bone pain or pruritis
• Ca * Po4 > 70
K/DOQI Clinical Practice Guidelines for Bone Metab and Disease in CKD. Am J Kidney Dis 2003
Dumasias, Oto Clinic N America 2010
Hyperparathyroidism
Cinacalcet (Sensipar)
• Calcimimetic
• Increases the sensitivity of the calcium-sensing
receptor to circulating serum calcium
• Does not improve bone density
• FDA approved for
– HPT in patients with chronic kidney disease
– severe hypercalcemia in patients with PHPT who
cannot undergo surgery
– Treatment of hypercalcemia in patients with
parathyroid carcinoma
Duntas, Endocrine 2011
www.fda.gov
Hyperparathyroidism
ESRD/HPT operative management
• Subtotal vs total with autotransplantation
• Often require calcium gtt & high doses of
Rocaltrol post-op, due to hungry bone
syndrome
K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003.
Dumasias. Oto Clinic N America. 2010.
Hyperparathyroidism
SUMMARY
1. 80% of patients with primary HPT are asymptomatic
2. Parathyroidectomy results in increased BMD and perhaps QOL
3. Many observed patients would benefit from surgery
4. Low morbidity surgery will benefit the majority of patients
5. Patients with normocalcemic HPT may benefit from surgery
Hyperparathyroidism
Contact information
Jennifer L Marti MD
Endocrine & Breast Surgery
Beth Israel Medical Center
Tel 212 844 6234
Email jmarti@chpnet.org